Depression is a debilitating and recurring psychiatric disorder. Approximately half of the patients with depressive disorder fail to respond to currently available antidepressants. The long-term goal of this project is to understand the pathogenesis of depressive disorders and to develop new therapeutic approaches for this disease. This is a resubmission of the application for competitive renewal of our current funding to study the molecular and cellular mechanisms underlying the antidepressant-like effect of the adipocyte- derived hormone, leptin. We have provided strong evidence that leptin possesses antidepressant-like properties, supporting a new adipostatic hypothesis of depression. Direct infusion of leptin into the hippocampus produces antidepressant-like effects, and ablation of the functional leptin receptor, LepRb, in this brain region induces depressive-like behaviors, suggesting an essential role of LepRb in the hippocampus in mediating leptin action on depressive behaviors. We have made novel observations that ablation of LepRb principally in forebrain glutamatergic neurons (Lepr cKO) leads to depressive-like symptoms and facilitates NMDA-induced synaptic depression in the hippocampus. The antidepressant-like behavioral effects of leptin were abolished in Lepr cKO mice. These mice were resistant to selective serotonin reuptake inhibitor (SSRI) treatments but highly responsive to the glutamate receptor NMDA- NR2B (also termed GluN2B) antagonist. These findings led to the hypothesis that the glutamatergic system mediates leptin action on depressive behaviors. We propose to determine 1) the role of hippocampal glutamate neurotransmission in mediating the antidepressant-like effects of leptin, and 2) the contribution of remodeling of hippocampal dendritic spines, sites of glutamatergic synapses, to the antidepressant-like effects of leptin. These studies will generate novel insights into molecular and cellular mechanisms into leptin action in the limbic system and lead to the development of novel therapies for depression. PUBLIC HEALTH RELEVANCE: Major depression is a severe and recurrent mental illness that is highly prevalent worldwide. Currently available antidepressant drugs are only effective in a subset of patients, and the onset of therapeutic actions requires weeks to months of treatment. The goals of this research project are to understand the mechanisms of the pathophysiology and pathogenesis of depression-related behaviors and to identify novel molecular and neural targets for treatments.